Elimination of GD3 synthase improves memory and reduces amyloid-β plaque load in transgenic mice

Alexandra Bernardo, Fiona E. Harrison, Meghan McCord, Jiali Zhao, Aleksandra Bruchey, Sean S. Davies, L. Jackson Roberts, Paul M. Mathews, Yasuji Matsuoka, Toshio Ariga, Robert K. Yu, Rebecca Thompson, Michael Mcdonald

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Gangliosides have been shown to be necessary for β-amyloid (Aβ) binding and aggregation. GD3 synthase (GD3S) is responsible for biosynthesis of the b- and c-series gangliosides, including two of the four major brain gangliosides. We examined Aβ-ganglioside interactions in neural tissue from mice lacking the gene coding for GD3S (St8sia1), and in a double-transgenic (APP/PSEN1) mouse model of Alzheimer's disease cross-bred with GD3S-/- mice. In primary neurons and astrocytes lacking GD3S, Aβ-induced cell death and Aβ aggregation were inhibited. Like GD3S-/- and APP/PSEN1 double-transgenic mice, APP/PSEN1/GD3S-/- "triple-mutant" mice are indistinguishable from wild-type mice on casual examination. APP/PSEN1 double-transgenics exhibit robust impairments on a number of reference-memory tasks. In contrast, APP/PSEN1/GD3S-/- triple-mutant mice performed as well as wild-type control and GD3S-/- mice. Consistent with the behavioral improvements, both aggregated and unaggregated Aβ and associated neuropathology were almost completely eliminated in triple-mutant mice. These results suggest that GD3 synthase may be a novel therapeutic target to combat the cognitive deficits, amyloid plaque formation, and neurodegeneration that afflict Alzheimer's patients.

Original languageEnglish (US)
Pages (from-to)1777-1791
Number of pages15
JournalNeurobiology of Aging
Volume30
Issue number11
DOIs
StatePublished - Nov 1 2009

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Amyloid Plaques
Transgenic Mice
Gangliosides
Amyloid
Astrocytes
Alzheimer Disease
Cell Death
Neurons
Brain
Genes

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Elimination of GD3 synthase improves memory and reduces amyloid-β plaque load in transgenic mice. / Bernardo, Alexandra; Harrison, Fiona E.; McCord, Meghan; Zhao, Jiali; Bruchey, Aleksandra; Davies, Sean S.; Jackson Roberts, L.; Mathews, Paul M.; Matsuoka, Yasuji; Ariga, Toshio; Yu, Robert K.; Thompson, Rebecca; Mcdonald, Michael.

In: Neurobiology of Aging, Vol. 30, No. 11, 01.11.2009, p. 1777-1791.

Research output: Contribution to journalArticle

Bernardo, A, Harrison, FE, McCord, M, Zhao, J, Bruchey, A, Davies, SS, Jackson Roberts, L, Mathews, PM, Matsuoka, Y, Ariga, T, Yu, RK, Thompson, R & Mcdonald, M 2009, 'Elimination of GD3 synthase improves memory and reduces amyloid-β plaque load in transgenic mice', Neurobiology of Aging, vol. 30, no. 11, pp. 1777-1791. https://doi.org/10.1016/j.neurobiolaging.2007.12.022
Bernardo, Alexandra ; Harrison, Fiona E. ; McCord, Meghan ; Zhao, Jiali ; Bruchey, Aleksandra ; Davies, Sean S. ; Jackson Roberts, L. ; Mathews, Paul M. ; Matsuoka, Yasuji ; Ariga, Toshio ; Yu, Robert K. ; Thompson, Rebecca ; Mcdonald, Michael. / Elimination of GD3 synthase improves memory and reduces amyloid-β plaque load in transgenic mice. In: Neurobiology of Aging. 2009 ; Vol. 30, No. 11. pp. 1777-1791.
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